Striatal Dopaminergic Innervation Research Articles

Immunophilin ligands can prevent progressive dopaminergic degeneration in animal models of Parkinson's disease.

Slowing or halting the progressive dopaminergic (DA) degeneration in Parkinson's disease (PD) would delay the onset and development of motor symptoms, prolong the efficacy of pharmacotherapies and decrease drug-induced side-effects. We tested the potential of two orally administered novel immunophilin ligands to protect against DA degeneration in two animal models of PD. First, in an MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model, we compared an immunophilin ligand (V-10,367) documented to bind the immunophilin FKBP12 with V-13,661, which does not bind FKBP12. Both molecules could prevent the loss of striatal DA innervation in a dose-dependent fashion during 10 days of oral administration. Second, to determine whether an immunophilin ligand can protect against progressive and slow DA degeneration typical of PD, an intrastriatal 6-hydroxydopamine-infusion rat model was utilized. Oral treatment with the FKBP12-binding immunophilin ligand began on the day of lesion and continued for 21 days. At this time point, post mortem analyses revealed that the treatment had prevented the progressive loss of DA innervation within the striatum and loss of DA neurons within the substantia nigra, related to functional outcome as measured by rotational behaviour. Notably, DA fibres extending into the area of striatal DA denervation were observed only in rats treated with the immunophilin ligand, indicating neuroprotection or sprouting of spared DA fibres. This is the first demonstration that immunophilin ligands can prevent a slow and progressive DA axonal degeneration and neuronal death in vivo. The effects of orally administered structurally related immunophilin ligands in acute and progressive models of DA degeneration are consistent with the idea that these compounds may have therapeutic value in PD.

The small molecule FKBP ligand GPI 1046 induces partial striatal re-innervation after intranigral 6-hydroxydopamine lesion in rats

Extensive unilateral striatal deafferentation was produced by intranigral 6-hydroxydopamine (6-OHDA) in rats. Beginning 60 days after 6-OHDA injection animals received a 14-day course of treatment with either the small molecule FKBP ligand GPI 1046 (10 mg/kg) or its vehicle alone. Striatal dopaminergic innervation density was determined from high power image analysis of striatal tyrosine hydroxylase (TH) immunohistochemistry. GPI 1046 treatment did not alter TH fiber density in the contralateral striatum but did produce significantly higher striatal TH fiber density in the ipsilateral caudate-putamen. This striatal re-innervation occurred in the absence of increased nigral sparing, and appears to reflect the GPI 1046 induced sprouting of residual TH+ fibers spared by the 6-OHDA lesion.

Decreased striatal dopaminergic innervation in REM sleep behavior disorder.

REM sleep behavior disorder (RBD) is a possible herald of neurodegenerative disorders with parkinsonism. The authors determined the density of striatal dopaminergic terminals with [11C]dihydrotetrabenazine PET in six elderly subjects with chronic idiopathic RBD and 19 age-appropriate controls. In subjects with RBD, there were significant reductions in striatal [11C]dihydrotetrabenazine binding, particularly in the posterior putamen.

Decreased striatal monoaminergic terminals in Huntington disease.

To evaluate the integrity of the dorsal striatal dopaminergic innervation in rigid and choreic Huntington disease (HD). Some patients with HD have an akinetic-rigid phenotype. It has been suggested that nigrostriatal in addition to striatal pathology is present in this subgroup. The authors sought to determine whether in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding could distinguish patients with akinetic-rigid (HDr) from typical choreiform (HDc) HD. Nineteen patients with HD (mean age 48 +/- 16 years) and 64 normal controls (mean age 50 +/- 14 years) underwent (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) PET imaging. DTBZ blood to brain ligand transport (K1) and tissue to plasma distribution volume (DV) in the caudate nucleus, anterior putamen, and posterior putamen were normalized to the occipital cortex. The normalized striatal specific DV was reduced in HDr (n = 6) when compared with controls: caudate nucleus -33% (p < 0.001), anterior putamen -56% (p < 0.0001), and posterior putamen -75% (p < 0.0001). Patients with HDc (n = 13) also had reduced striatal DV: caudate nucleus -6% (NS), anterior putamen -19% (p < 0.01), and posterior putamen -35% (p < 0.0001). Patients with HDr had significantly lower striatal (+)-alpha-[11C]DTBZ binding than HDc patients. After correction for tissue atrophy effects, normalized DV differences were less significant, with values somewhat increased in the caudate, slightly reduced in the anterior putamen, and moderately decreased in the posterior putamen. There were no significant regional differences in K1 reductions among caudate, anterior, and posterior putamen in HD. Reduced striatal VMAT2 binding suggests nigrostriatal pathology in HD, most severely in the HDr phenotype. Striatal DV reductions were most prominent in the posterior putamen, similar to PD.

Striatal presynaptic monoaminergic vesicles are not increased in Tourette’s syndrome

Abnormal function of striatal dopaminergic synapses is suggested to underlie Tourette's syndrome (TS). To determine dorsal striatal dopaminergic innervation in TS. Prior in vitro and in vivo studies of dopamine reuptake transporter binding sites suggest increased striatal dopaminergic innervation in TS. We used in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding to quantify striatal dopaminergic innervation in TS. Eight TS patients (mean age 30+/-9 years) and 22 age-comparable normal controls (age 34+/-8 years) underwent PET imaging with the VMAT2 ligand (+)-alpha-[11C]dihydrotetrabenazine (DTBZ). Compartmental modeling was used to quantify blood-to-brain ligand transport and VMAT2 binding site density from the tissue-to-plasma distribution volume (DV) during continuous (+)-alpha-[11C]DTBZ infusion. DTBZ DV in dorsal striatal regions was expressed relative to the occipital cortex to estimate relative specific VMAT2 binding (binding potential). We found no significant differences in VMAT2 binding potential between patients and controls in the caudate nucleus, anterior putamen, or posterior putamen. There were no significant differences in striatal VMAT2 binding between patients with (n = 5) or without (n = 3) features of obsessive-compulsive disorder. There is no evidence for increased binding to the VMAT2 in TS striatum and that dorsal striatal dopaminergic innervation density is normal in TS. The previously reported changes in dopamine transporter binding sites may reflect medication effect and/or altered synaptic activity or regulation of dopamine transporter expression in nigrostriatal neurons.

(+)-alpha-[11C]Dihydrotetrabenazine PET imaging in familial paroxysmal dystonic choreoathetosis.

Clinical observations suggest a disturbance of striatal dopaminergic function in familial paroxysmal dystonic choreoathetosis (PDC). The authors used PET with [11C]dihydrotetrabenazine (DTBZ) to study striatal dopaminergic innervation in PDC. The results did not reveal abnormal DTBZ binding potential in PDC striatum. This suggests that dopaminergic abnormalities, if present, may be due to altered regulation of dopamine release or to postsynaptic mechanisms, rather than to an altered density of nigrostriatal innervation.

Reduced striatal dopaminergic innervation shown by IPT and SPECT in patients under neuroleptic treatment: need for levodopa therapy?

We investigated the availability of dopamine reuptake sites in the striata of two patients with productive symptoms and neuroleptic therapy as well as progressive parkinsonism using the new dopamine transporter ligand [ 123I] N-(3-iodopropen-2-yl)-2β-carbo-methoxy-3β-(4-chlorophenyl)tropane (IPT) and single photon emission computed tomography (SPECT). Normal specific binding in the caudate nucleus was 8.6±1.2 and in the putamen 6.5±1.3 (mean±S.D.; n=8; mean age, 56.7 years; range 41–67 years). Patient 1 (age 43) was admitted to our clinic at age 38 because of left-sided parkinsonism. At age 40, she developed paranoid psychosis without change after cessation of l-DOPA and lisuride treatment for 3 months. She was diagnosed as a schizophrenic, paranoid subtype (DSM-III-R). IPT–SPECT showed a loss of dopaminergic nerve terminals (right caudate/putamen, 5.16/2.0; left caudate/putamen, 5.92/2.66). Patient 2 (age, 61 years) had a history of paranoid psychosis for approx. 30 years. He experienced progressive right-sided parkinsonism since age 57 when treated with clozapine. IPT–SPECT showed a marked reduction of striatal dopamine transporter binding (right caudate/putamen, 5.06/1.65; left caudate/putamen, 3.8/1.12). Our findings indicate that patients may suffer contemporaneously from Parkinson's disease and schizophrenia. In these patients, the proof of a nigrostriatal dopaminergic deficit justifies treatment with neuroleptics and dopaminergic drugs. Imaging of dopamine transporters with SPECT and IPT or a related compound represents an attractive alternative to the more complex measurements of fluorodopa uptake with positron emission tomography (PET). © 1998 Elsevier Science Ireland Ltd. All rights reserved.

Compensatory mechanisms in experimental and human Parkinsonism: towards a dynamic approach

This paper provides an overview of the compensatory mechanisms which come into action during experimental and human parkinsonism. The intrinsic properties of the dopaminergic neurones of the substantia nigra pars compacta (SNc) which degenerate during Parkinson's disease are described in detail. It is generally considered that the nigrostriatal pathway is principally responsible for the compensatory preservation of dopaminergic function. It is also becoming clear that the morphological characteristics of dopaminergic neurones and the dual character, synaptic and asynaptic, of striatal dopaminergic innervation engender two modes of transmission, wiring and volume, and that both these modes play a role in the preservation of dopaminergic function. The plasticity of the dopamine neurones, extrinsic or intrinsic to the striatum, can thus be regarded as another compensatory mechanism. Recent anatomical and electrophysiological studies have shown that the SNc receives both glutamatergic and cholinergic inputs. The dynamic role this innervation plays in compensatory mechanisms in the course of the disease is explained and discussed. Recent developments in the field of compensatory mechanisms speak for the urgence to develop a valid chronic model of Parkinson's disease, integrating all the clinical features, even resting tremor, and illustrating the gradual evolution of nigral degeneration observed in human Parkinson's disease. Only a dynamic approach to the physiopathological study of compensatory mechanisms in the basal ganglia will be capable of elucidating these complex questions.

Regulation of the Nigrostriatal Pathway by Metabotropic Glutamate Receptors during Development

Dopamine neurons in the substantia nigra heavily innervate the striatum, making it the nucleus with the highest levels of dopamine in the adult brain. The present study analyzes the time course and the density of striatal innervation by nigral dopamine neurons and characterizes the role of the neurotransmitter glutamate during the development of the nigrostriatal pathway. For this purpose, organotypic cultures containing the cortex, the striatum, and the substantia nigra (triple cultures) were prepared from rat brains at postnatal day (PND) 0-2 and were cultured for up to 60 d in vitro (DIV). Dopamine fibers and neurons were labeled using tyrosine hydroxylase (TH) immunohistochemistry. Striatal TH-ir fiber density was quantitatively analyzed using confocal laser scanning microscopy (CLSM). In long-term triple cultures (44 +/- 3 DIV), the striatal dopamine fiber density was high and was weakly correlated with the number of nigral dopamine neurons. The high striatal dopamine fiber density mainly resulted from an enhanced ingrowth and ramification of dopamine fibers from nigral neurons during 8-17 DIV. The metabotropic glutamate receptor (mGluR) antagonist L(+)-2-amino-3-phosphonopropionic acid (L-AP-3) selectively inhibited this dopaminergic innervation of the striatum, whereas ionotropic GluR antagonists had no effect. The L-AP-3-mediated inhibition was prevented by the mGluR agonist 1S, 3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD). The inhibition of the striatal dopaminergic innervation by L-AP-3 was further confirmed by anterograde tracing of the nigrostriatal projection with Phaseolus vulgaris leucoagglutinin. These results indicate that glutamate, by acting on group I mGluRs, plays an important "trophic" role for the development of the nigrostriatal dopamine pathway.

Arginine-aspartate and haloperidol-induced neurobehavioral effects in the rat

This study determined the effects, in the rat, of 8-day treatment with arginine-aspartate on haloperidol-induced catalepsy, decrease of locomotor activity and change of striatal dopamine, homovanillic acid (HVA) and dihydroxy-phenylacetic acid (DOPAC) content. Arginine-aspartate was able to attenuate the haloperidol-induced decrease of locomotor activity and to significantly reduce the catalepsy. Moreover, arginine-aspartate treatment itself increased striatal dopamine content and produced a significant decrease of the HVA/dopamine ratio. Pretreatment with arginine-aspartate was able to partially counteract the haloperidol-induced changes of dopamine metabolism: the haloperidol-induced increases of the DOPAC/dopamine and HVA/dopamine ratios were significantly reduced in arginine-aspartate- pretreated rats. These results suggest that the action of arginine-aspartate on haloperidol-induced neurobehavioral effects is probably mediated by interference with striatal dopaminergic innervation.

Intrastriatal transplants of embryonic dopaminergic neurons counteract the increase of striatal enkephalin immunostaining but not serotoninergic sprouting elicited by a neonatal lesion of the nigrostriatal dopaminergic pathway.

The aim of the our experiment was to compare the ability of intrastriatal implants of embryonic dopaminergic neurons to reverse two kinds of postlesion modification in the host brain: the change in the activity level of neurons in the denervated area and morphological modifications, e.g. collateral sprouting. The ascending dopaminergic system of 3-day-old rat pups was unilaterally lesioned by an intrahypothalamic injection of the neurotoxin 6-hydroxydopamine. This lesion has been described previously to induce an increase in the level of activity of striatal enkephalinergic neurons. The same lesion leads also to sprouting of the serotoninergic afferents in the striatum, leading to hyperinnervation of this structure. The existence of these modifications thus offers the possibility of testing the influence of grafts in one structure of the same animal on two lesion-induced reactions of different nature. A cell suspension obtained from mesencephali of embryonic day 14 rats and containing dopaminergic neurons was implanted into the denervated striatum of lesioned animals 5 days after the lesion. Nine months later the animals were killed and immunohistochemistry was performed on striatal sections using antibodies directed against tyrosine hydroxylase, methionine enkephalin and serotonin. Intensity of immunostaining (methionine enkephalin and serotonin) as well as innervation density (serotonin) was quantified through the use of a computer-assisted image analyser. The lesion led to the disappearance of striatal dopaminergic innervation. Implanted dopaminergic neurons were found scattered in the striatum and restored a dopaminergic innervation in a large portion of this structure. There was a marked increase in striatal methionine enkephalin immunostaining in lesioned animals, which was most pronounced in the dorsolateral part of the striatum (+ 150% compared to control values), while in the ventral part it was slight or non-existent. The density of striatal serotoninergic innervation was also increased by approximately 250% relative to control values. In grafted animals striatal enkephalin immunostaining was similar to that observed in control animals. On the other hand, the serotoninergic hyperinnervation was still present in the graft-bearing striata. These results suggest that while intrastriatal implants of embryonic dopaminergic neurons are able to counteract modifications in the functioning of local striatal neuronal systems such as the increase in enkephalinergic activity or receptor hypersensitivity occurring as a result of the lesion, they might be unable to reverse postlesion morphological modifications.

Hypertrophy of dopamine neurons in the primate following ventromedial mesencephalic tegmentum lesion

Morphological changes in ventral mesencephalic dopamine (DA) neurons of a monkey sustaining a unilateral electrolytic lesion of the ventromedial mesencephalic tegmentum four years earlier were examined. Substantia nigra (A9) DA neurons lateral to the lesion underwent hypertrophic changes. The mean area of these neurons was enlarged by approximately 30% relative to corresponding neurons in the contralateral substantia nigra. Semi-quantitative immunohistochemical measurements of the intensity of tyrosine hydroxylase-like immunoreactivity (TH-li) indicated an increase in the amount of TH-li protein per cell in the hypertrophied neurons. Hypertrophic changes were also observed in ipsilateral A11 DA neurons of the caudal hypothalamus, suggesting that the increase in size was related to transection of the axons of DA neurons as they pass through the midbrain in their projections to target sites. The lesion did not overtly change the density or pattern of the substance P innervation of the substantia nigra, indicating that the striato- and pallido-nigral projections were spared by the lesion. These data suggest that hypertrophy may be a compensatory mechanism of dopaminergic neurons in response to partial lesions of the nigrostriatal system, and thus represent a morphological counterpart to the compensatory biochemical processes effected in response to partial lesions of the striatal dopaminergic innervation.

Striatal glutamic acid decarboxylase immunoreactivity is increased after dopaminergic deafferentation: densitometric analysis

Several lines of evidence suggest that dopamine exerts a chronic inhibitory action on GABAergic cells in the striatum, and striatal glutamic acid decarboxylase (GAD) mRNA levels are increased after ipsilateral dopaminergic deneveration. In the present study we have used GAD immunocytochemistry to assess whether dopaminergic denervation results in an increase in GAD protein synthesis. In three 6-hyroxydopamine-lesioned animals, there was a perceptible increase in the density of GAD-immunoreactive (ir)staining on the side ipsilateral to the lesion. Computer-assisted densitometric analysis showed a significant increase in GAD-ir staining in the ipsilateral striatum compared to the contralateral (control) side. These data suggest that removal of striatal dopaminergic innervation results in an increase in the amount of immunoreactive GAD, the rate limiting enzyme in the synthesis of GABA.

Dopamine high-affinity transport site topography in rat brain: Major differences between dorsal and ventral striatum

Investigations were conducted to determine the topography of the high-affinity dopamine uptake process within the rat striatum. [ 3H]Dopamine uptake into crude synaptosomes prepared from micropunch samples was found to be two- to three-fold higher in dorsal caudate-putamen relative to nucleus accumbens septi. In contrast, the concentrations of dopamine in the two regions were equivalent. The recognition site associated with high-affinity dopamine uptake was labeled using [ 3H]mazindol, and the binding of this ligand was also found to be two- to three-fold higher in homogenates from dorsal caudate-putamen samples relative to nucleus accumbens septi. Regional differences in uptake of [ 3H]dopamine or binding of [ 3H]mazindol were shown to be due to variations in V max or B max, not to differences in apparent affinity. Autoradiography of [ 3H]mazindol binding in rat striatum revealed a decreasing density of the site along the dorsal-to-ventral axis, with the highest binding occurring in the dorsolateral caudate-putamen, lower binding in the ventral caudate-putamen, and lowest levels in the septal pole of the nucleus accumbens septi. Quantification showed that the extent of this gradient was two-fold. Further autoradiographic studies revealed less striatal heterogeneity in the pattern of binding of [ 3H]ketanserin, another radioligand associated with the striatal dopaminergic innervation but not linked to the dopamine uptake process of the plasma membrane. The findings suggest that the dopaminergic fibers of the ventral striatum, especially the medial nucleus accumbens septi, may be relatively lacking in their capacity for dopamine uptake following its release. This organization may result in regional differences in the time-course of extraneuronal dopamine following transmitter release and may render the dopamine-containing terminals of the ventral striatum less susceptible to the degenerative influences of neurotoxins that are incorporated by the high-affinity dopamine uptake process.

Compartment-specific changes in the density of choline and dopamine uptake sites and muscarinic and dopaminergic receptors during the development of the baboon striatum: a quantitative receptor autoradiographic study.

In the fetal and young primate neostriatum, cholinergic and dopaminergic markers show patches of high density surrounded by a lower-density matrix. In the adult, the same markers display the opposite pattern, a lower density in striosomes, surrounded by a higher-density matrix. In order to understand the developmental sequences leading to the adult compartmental organization of the primate neostriatum, a quantitative technique was used to study the ontogeny of pre- and postsynaptic components of cholinergic and dopaminergic neurons in baboon caudate nucleus and putamen. The development of specific uptake mechanisms for choline and dopamine and receptors was studied by means of quantitative autoradiography of the specific binding of [3H]-hemicholinium-3 [( 3H]-HC3) and [3H]-mazindol [( 3H]-MAZ) to the choline and dopamine uptake systems, respectively. [3H]-pirenzepine [( 3H]-PIR) was used to label M1 muscarinic receptors and [3H]-spiroperidol [( 3H]-SPI) was used to label striatal dopamine D2 receptors. Serial sections were used for each ligand to determine the precise anatomical relationships between the binding patterns of the different markers. Our aim was to determine whether the adult striosomal distribution of the binding sites studied was due to 1) a selective decrease in patch/striosomal binding density or 2) a selective increase in matrix binding density. Our studies show that a postnatal decrease in the density of [3H]-HC3 sites in the patch/striosomes and an increase in the matrix density of [3H]-MAZ sites are the primary, but not the sole, changes in the compartmental distribution of these sites leading to the adult striosomal organization of the striatal cholinergic and dopaminergic innervation. D2 receptors follow the general developmental pattern of [3H]-MAZ and [3H]-HC3, changing their density of distribution in both compartments during the developmental period examined. In addition, M1 muscarinic receptors already display their adult pattern in the newborn baboon striatum, and therefore represent one of the first neurochemical makers to adopt its mature organization.

Striatal dopamine deficiency in Parkinson's disease: role of aging.

The striatal dopaminergic innervation was investigated postmortem in 49 control and 57 parkinsonian brains by assessing the binding of tritiated alpha-dihydrotetrabenazine ([3H]TBZOH), a specific ligand of the vesicular monoamine transporter. The density of [3H]TBZOH binding sites in the caudate nucleus of control subjects decreased significantly with age, suggesting an age-dependent reduction in striatal dopamine innervation. In contrast, an increase with the age at time of death was observed in patients with Parkinson's disease, although the density of [3H]TBZOH binding sites was subnormal. Mean values represented 26.5% and 12.7% of control values in the caudate nucleus and in the putamen, respectively. The binding of [3H]TBZOH in the caudate nucleus decreased exponentially with the duration of Parkinson's disease. The rate of [3H]TBZOH binding decrease, an index of the rate of striatal dopaminergic denervation, was about twice as high in parkinsonian patients as in controls and was not related to the age at onset of the disease. The data suggest that (1) parkinsonian symptoms appear above a threshold degeneration state corresponding to 50% of the normal innervation at the age of 60, and (2) aging does not play a major role in the process of nigrostriatal neuron degeneration in Parkinson's disease.

Developmental expression of proenkephalin mRNA and peptides in rat striatum

The development of proenkephalin (PE) gene expression in the rat striatum was examined at the mRNA and peptide levels. Immunocytochemistry was performed with antisera generated to the PE-specific peptide product Met-enkephalin-Arg-Gly-Leu (MERGL). The distribution of immunostaining was compared with the distribution of PE mRNA, determined by in situ hybridization with an oligonucleotide probe. PE mRNA first appeared at E16 in the caudal ventrolateral striatum, followed at E17–18 by the appearance of MERGL immunoreactivity in a similar distribution. The anatomical gradients of PE gene expression were similar to the pattern of histogenesis of striatal neurons, suggesting that the timing of PE gene expression is related to the time of neuronal withdrawal from the mitotic cycle. The relation of the development of PE gene expression to the known patterns of striatal histogenesis, neurochemical compartmentalization and dopaminergic innervation is discussed.

Time course of postmortem modifications in synaptosomal [ 3H]dopamine uptake and [ 3H]GBR 12783 binding to the dopamine uptake complex in the rat striatum

The present study focuses on the changes of two biochemical markers of the striatal dopaminergic innervation evaluated after different postmortem storage periods of rat heads either at room temperature (21°C) or at 4°C: (i) the uptake of [ 3H]dopamine (DA) into striatal synaptosomes and (ii) the specific binding of [ 3H]GBR 12783, a selective ligand for the neuronal dopamine uptake sites, to a striatal membrane fraction. The uptake of [ 3H]DA was completely abolished after 24 and 72 h storage of the tissue at 21°C and 4°C, respectively, whereas in the same conditions, the binding of [ 3H]GBR 12783 was slightly decreased. The K m and K d of these two processes were virtually unchanged after the different storage periods considered, whereas the V max and B max were markedly decreased.

The pre- and postnatal development of the dopaminergic cell groups in the ventral mesencephalon and the dopaminergic innervation of the striatum of the rat

In the adult rat the striatum is a compartmentalized structure, which is reflected in the inhomogeneous distribution of dopamine. As a first step to test the hypothesis that dopamine plays an organizational role in the development of the striatum, the ontogeny of the dopaminergic system was studied in detail with immunocytochemical methods employing antibodies against dopamine. Rat embryos, fetuses, pups and adults were perfusion-fixed with glutaraldehyde on all prenatal days from E11 onward, postnatally on P2, P4, P6, P7, P8, P13, P14, P20, P21, and in adult age. On E13 the first dopaminergic cells are detected in the ventral prosencephalon. On E14 two dopaminergic cell groups are present in the ventral mesencephalon, and fibres of these cells reach the ventrolateral part of the ganglionic eminence. In the next two days both the cell groups and their projections rapidly increase in size. On E17 the afferent dopaminergic fibres to the striatum become aligned and form huge bundles that are closely associated with the fascicles of the internal capsule. Rostrally, the development of the striatal dopaminergic innervation shows a clear ventrolateral to dorsomedial gradient, whereas more caudally the dopaminergic fibres innervate the striatum from a ventromedial position. The lateral parts of the otherwise compact mesencephalic cell groups consist of loosely arranged cells. From E17 onward these cells become arranged into a dorsal and a ventral group. Just before birth, on E21, the primordia of the dopaminergic cell groups in the substantia nigra pars compacta and pars reticulata can be observed. On E19 several centres with extensive fibre ramifications along the dorsolateral margin of the caudate putamen represent the first signs of the inhomogeneous distribution of dopaminergic fibres in the dorsal striatum seen during the next two weeks. In the following pre- and postnatal days these so-called dopaminergic “patches” also appear more medially. By the third postnatal week most of the patches are no longer detectable, and only the most dorsolaterally located ones, i.e. in the region where they first were detected on E19, remain visible through to the adult stage. Prenatally, no varicosities can be observed in the dopaminergic fibres. The first varicosities appear after birth. Their number increase rapidly during the first and second postnatal weeks and reaches near adult levels on P20. The development of the striatal dopaminergic innervation, and that of the “patches” in particular, is discussed in relation to the development of the mesencephalic dopaminergic cell groups. On the basis of the present results and those of thymidine autoradiographic studies the inference can be made that the developmental pattern of the dopaminergic innervation of the striatum and the pattern of neurogenesis of this area are closely related.

Nocturnal rotational behavior in rats: Further neurochemical support for a two-population model

The relationship between circling behavior and the concentrations of dopamine (DA), serotonin, and their metabolites in corpus striatum was investigated in rats. We have previously reported evidence indicating that in both sexes there are two kinds, or populations, of rats: those with their turning biases directed away from (Contra〉Ipsi rats), and those with their turning biases directed towards (Ipsi〉Contra rats), the side containing the striatum with the greater dopaminergic innervation. In the present experiment rats were classified according to whether the contralateral or ipsilateral striatum contained the greater dopamine concentration. Whereas the ipsilateral striata were found to contain the same concentrations of dopamine, the contralateral sides were found to differ significantly; and the difference between the contralateral and ipsilateral dopamine concentrations was significantly correlated with the contralateral, but not the ipsilateral, dopamine concentration. These results are identical to those we previously reported using the Vmax for dopamine uptake in vitro as the measure for striatal dopaminergic innervation. As an initial attempt to determine what neurochemical mechanisms might underlie the differences between the “Contra〉Ipsi” and “Ipsi〉Contra” rats, it was found that dopamine turnover, as measured by the ratios of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid to DA, was higher in the striata of the latter group than in the former group. The present results are discussed in terms of their support for the two-population model, and in relation to previous work on behavioral and neurochemical asymmetry in rats.